The following discussion of the background art is intended to facilitate an understanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge as at the priority date of the application.
Diabetes mellitus (diabetes) is a chronic metabolic disorder affecting hundreds of millions of people worldwide, where the hormone insulin, is not produced in sufficient amounts or peripheral tissues are not sensitive enough to this hormone to efficiently convert glucose in the blood into energy. Hence, diabetes is caused by an absolute or relative insulin deficiency. The former causes mainly Type 1 diabetes as the result of autoimmune destruction of insulin-producing cells, and the latter causes Type 2 diabetes as a progression of insulin resistance.
Abnormalities of glucose metabolism as a result of insulin deficiency can produce acute, potentially life-threatening metabolic disturbances as well as chronic, vascular complications with significant morbidity and mortality. In addition to its physical and psychological effects, the treatment burden of the disease is considerable, as it requires a major adjustment to everyday activities including diet, exercise, occupation and recreational activities. At present, the only routinely available therapy is exogenously administered insulin given as either multiple daily injections or continuous subcutaneous infusion (pump). The ultimate goal, therefore, would be to cure the disease by generating a renewable source of transplantable human, insulin-secreting β cells in vitro and/or to regenerate endogenous β cells in vivo, should autoimmunity be controlled.
The normal pancreas has about one million islets, and although a person can lose over 80% of these before diabetes develops, transplanting far more than 20% of the total seems to be necessary before blood sugars can be corrected. Laboratories such as Islet Sheet Medical in San Francisco estimate 700,000 islets are needed for total reversal of diabetes.
Differentiation of functional insulin-secreting β cells from a variety of less specialised, stem and/or progenitor cells for use in replacement cell therapy as a cure for Type 1 diabetes has, therefore, been the focus of intensive research over the last decade, aiming for a fundamentally better, long-term way to manage the disease. The development of stem cell or other cell-based treatment of diabetes, known collectively as cellular therapy, has the potential to restore normal glycaemic control in diabetes, and is the most important focus of companies with long-term vision in the field of diabetes management.
The ability to differentiate embryonic stem cells into insulin-secreting cells initially showed great promise, but functional β cells have so far not been produced in vitro. Currently, there are no cellular therapy products present in the market. A recently planned clinical trial for a potential new commercial product has been limited by the fact it requires at least 4 months (even in mice) after transplantation before cell maturity is reached and hyperglycaemia is controlled, and co-administration of insulin is also required.
Some progress has been made with differentiation of insulin-secreting β cells, including demonstration of insulin-producing β cells from culture of heterogeneous cellular populations from various sources, such as adult pancreatic ductal epithelium and acinar tissue. Hyperglycemia could be reversed after transplantation in some studies. Nevertheless, no evidence was provided that these β cells were indeed differentiated from defined animal or human pancreatic/islet progenitors; nor purified populations have been shown to give rise to mature endocrine cells in an in vitro system.
Therefore, replacement cell therapy as a cure for Type 1 diabetes is held back by a major impediment: functional insulin-secreting β cells have not yet been successfully differentiated from defined pancreatic progenitors or any other stem cell and/or progenitor source. This is as a result of a significant lack of knowledge of the signals that regulate late differentiation and maturation of islet cells, a dearth of specific markers for purification of their progenitors, as well as lack of an effective differentiation system within which the differentiation of these progenitors could occur.
It is against this background that the present invention has been developed.